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A platform for genome mining of multidrug-resistant pathogens to develop therapeutic phages using synthetic biology

利用合成生物学开发治疗性噬菌体的多重耐药病原体基因组挖掘平台

基本信息

批准号：
10356122
负责人：
Yoann Stephane Le Breton
金额：
$ 16.91万
依托单位：
GENEVA FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-18 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356122
关键词：
Address Antibiotic Resistance Antibiotics Antimicrobial Resistance Bacteria Bacteriophages Biology Biomedical Engineering Cell Surface Receptors Cells Centers for Disease Control and Prevention (U.S.)Chromosomes Cytolysis DNA sequencing Development Disease Endotoxins Engineering Environment Essential Genes Experimental Designs Genes Genetic Genetic Engineering Genome Genome engineering Goals Gold Horizontal Gene Transfer Human Infection Knowledge Learning Life Life Cycle Stages Lytic Lytic Phase Medical Methods Microbial Biofilms Mining Modality Modeling Modern Medicine Modification Monoclonal Antibodies Multi-Drug Resistance Mutation Patients Penicillin Resistance Pharmaceutical Preparations Preparation Production Property Prophages Reporting Resistance Rogaine Safety Sepsis Series Source Specificity Streptococcal Infections Streptococcus pyogenes Structure Testing Therapeutic Vaccines Virulence Virulence Factors Wound Infection antimicrobial arm bacterial resistance base design design-build-test efficacy testing experience functional genomics gene interaction global health high throughput analysis human pathogen in vivo in vivo Model insight interest multi-drug resistant pathogen pathogen pathogenic bacteria receptor research and development small molecule synthetic biology therapeutic target tool

项目摘要

PROJECT SUMMARY/ABSTRACT Multidrug resistant [MDR] pathogens represent a global health threat and a challenge for modern medicine; and, as bacterial resistance to new antibiotics is now outpacing the antibiotic development effort, it is critical to develop new effective antimicrobial alternatives. The antimicrobial resistance crisis is bringing new interests worldwide to develop phage-based therapies. Over the last decade, efforts in the U.S. to produce phage therapeutics targeting different bacterial pathogens have shown promising results, including successful treatments of life-threatening infections in human patients. Safety of phage therapy is still a concern in the U.S.; however FDA has highlighted requirements for phage preparation: they need to be safe, pure, potent, exclusively lytic, non-transducing, and lacking undesirable genes (antibiotic resistance, virulence factors) and bacterial endotoxins. If bacteriophages for therapy have historically been isolated from natural environments, recent progresses in phage genetics and genome engineering have proven successful to generate synthetic, strictly lytic derivatives targeting pathogens. The development of synthetic phages against MDR pathogens would require pipelines to accelerate our knowledge on newly discovered phages and their potential for synthetic biology. Critical insights into their biology, i.e. genome structure, phage replication cycle, genetic content (essential genes versus dispensable [antibiotic resistance and virulence genes]), interaction with the target host, are a prerequisite. Here, we propose a platform to (i) mine the genomes of MDR pathogens, a gold mine to identify dormant lysogenic phages directly from within their natural host; and (ii) develop high-throughput pipelines to quickly gain knowledge on the phage biology to guide our efforts to engineer synthetic phages as therapeutics. We will use the Group A Streptococcus (GAS), a “Concerning Threat” on the 2019 CDC “18 MDR pathogens” Watch List, as our model. We showed that Tn-seq could identify functional lysogenic phages from cryptic ones in GAS genomes, and mutations to reboot dormant prophages into their lytic cycle. In Aim 1, we will produce the critical knowledge to guide decision on what phages to select for therapeutic potential using synthetic biology: we will experimentally assess phage genome organization, phage replication/transduction mechanisms, host range and cell surface receptor(s). In Aim 2, we will implement a design-build-test-learn cycle" pipeline to optimize the synthetic biology effort, i.e. deletion of undesirable genes and addition of “payload” genes, to enhance their potential as therapy phages. Finally, we will use in vivo model of wound infection to test the efficacy of the synthetic phages we generated. Our overarching goal is to develop the tools and experience to apply our synthetic biology phage-engineering platform to other MDR pathogens.

项目总结/文摘